Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018801 (heart failure)
 72,216 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an established swine model of severe left ventricular (LV) hypertrophy (LVH), the bioenergetic and functional consequences of transplanting autologous mesenchymal stem cells (MSCs) overexpressing vascular endothelial growth factor (VEGF-MSCs) into the LV were evaluated; transplantation was accomplished by infusion of VEGF-MSCs into the interventricular cardiac vein. Specifically, the hypertrophic response to aortic banding was compared in seven pigs treated with 30 million VEGF-MSCs, eight pigs treated with 30 million MSCs without VEGF modification, and 19 untreated LVH pigs. Eight pigs without banding or cell transplantation (normal) were also studied. Four weeks postbanding, LV wall thickening (MRI), myocardial blood flow (MBF), high-energy phosphate levels ((31)P magnetic resonance spectroscopy), and hemodynamic measurements were obtained under basal conditions and during a catecholamine-induced high cardiac workstate (HCW). Although 9 of 19 untreated banded pigs developed clinical evidence of biventricular failure, no MSCs-treated animal developed heart failure. MSCs engraftment was present in both cell transplant groups, and both baseline and HCW MBF values were significantly increased in hearts receiving VEGF-MSCs compared with other groups (P < 0.05). During HCW, cardiac inotropic reserve (defined as the percent increase of rate pressure product at HCW relative to baseline) was normal in the VEGF-MSCs group and significantly decreased in all other banded groups. Additionally, during HCW, the myocardial energetic state [reflected by the phosphocreatine-to-ATP ratio (PCr/ATP)] of VEGF-MSCs-treated hearts remained stable, whereas in all other groups, PCr/ATP decreased significantly from baseline values (P < 0.05, each group). Myocardial von Willebrand factor and VEGF mRNA expressions and myocardial capillary density were significantly increased in VEGF-MSCs-treated hearts (P < 0.05). Hence, in the pressure-overloaded LV, transplantation of VEGF-MSCs prevents LV decompensation, induces neovascularization, attenuates hypertrophy, and improves MBF, myocardial bioenergetic characteristics, and contractile performance.
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PMID:Bioenergetic and functional consequences of stem cell-based VEGF delivery in pressure-overloaded swine hearts. 1638 94

Application of ultrasound-mediated destruction of microbubbles (US + Bubble) to skeletal muscle creates capillary ruptures leading to leakage of the cell components. We studied whether US + Bubble combined with bone-marrow-derived mononuclear cells (BM-MNCs) infusion enables the targeted delivery of endothelial-lineage cells into the myocardium and improves cardiac function of the cardiomyopathy model due to the paucity of neocapillary formation. Pulsed US was applied to the anterior chest of BIOTO2 cardiomyopathy hamsters for 90 s after the intravenous injection of microbubble (Optison) followed by infusion of BM-MNCs. Cardiac samples from US + microbubble + BM-MNCs (US + Bubble + BM), US + Bubble, US + BM without Bubble, and saline infusion control groups were analyzed 12 weeks after treatment. Labeled BM-MNCs transplanted by US + Bubble were found to be mainly localized in the microvessels, but not by US stimulation without microbubble (121.2 +/- 24.5 vs. 2.80 +/- 1.30 cells/mm2, P < 0.001). Capillary densities in US + Bubble + BM group were increased 1.7-fold (P < 0.05) over the control, and neither US + Bubble nor US + BM enhanced neocapillary formation. 99mTc-Tetrofosmin scintigraphy revealed that blood perfusion area in the US + Bubble + BM group was 48% greater than the control (P < 0.01). US + Bubble stimulation induces the expression of adhesion molecules (VCAM-1 and ICAM-1) in capillaries, and the US + Bubble-mediated supply of BM-MNCs increased the myocardial content of VEGF and bFGF. The left ventricular wt/body wt, area of cardiac fibrosis, and apoptotic cell numbers in the US + Bubble + BM group significantly (P < 0.05) decreased by 82%, 73%, and 64% relative to the control, respectively. The cardiac function in myopathic hamsters (assessed by fractional shortening) was markedly improved 36% (P < 0.05) by US + Bubble + BM treatment. Targeted delivery of BM-MNCs by US + Bubble to the myocardium of the cardiomyopathic hamster increased the capillary densities and regional blood flow and inhibited cardiac remodeling, resulting in the prevention of heart failure. This non-invasive cell delivery system may be useful as a novel efficient approach for angiogenic cell therapy to the myocardium.
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PMID:Myocardium-targeted delivery of endothelial progenitor cells by ultrasound-mediated microbubble destruction improves cardiac function via an angiogenic response. 1667

Hepatocyte growth factor (HGF) is an angiogenic factor upregulated in ischaemic diseases. We measured plasma HGF concentration in 26 patients (pts) with stable angina pectoris (SAP) and 16 pts with unstable angina pectoris (UAP). HGF levels were significantly higher in pts with UAP compared with pts with SAP (p<0,01), in pts with SAP vs control group (n=38, p<0,01) and in pts with UAP vs control group (p<0,001). HGF levels in SAP group correlated with heart failure symptoms (p=0,023). There was a trend towards significance between HGF and left ventricle ejection fraction (p=0,08) and between HGF and VEGF levels in pts with SAP (p=0,08). This study demonstrates that HGF plasma levels correlates with SAP symptoms. Pts with SAP and UAP has significantly higher levels of HGF comparing with control group.
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PMID:[Hepatocyte growth factor (HGF) in stable and unstable coronary heart disease]. 1673 98

Clinical trials of bone marrow stem/progenitor cell therapy after myocardial infarction (MI) have shown promising results, but the mechanism of benefit is unclear. We examined the nature of endogenous myocardial repair that is dependent on the function of the c-kit receptor, which is expressed on bone marrow stem/progenitor cells and on recently identified cardiac stem cells. MI increased the number of c-kit+ cells in the heart. These cells were traced back to a bone marrow origin, using genetic tagging in bone marrow chimeric mice. The recruited c-kit+ cells established a proangiogenic milieu in the infarct border zone by increasing VEGF and by reversing the cardiac ratio of angiopoietin-1 to angiopoietin-2. These oscillations potentiated endothelial mitogenesis and were associated with the establishment of an extensive myofibroblast-rich repair tissue. Mutations in the c-kit receptor interfered with the mobilization of the cells to the heart, prevented angiogenesis, diminished myofibroblast-rich repair tissue formation, and led to precipitous cardiac failure and death. Replacement of the mutant bone marrow with wild-type cells rescued the cardiomyopathic phenotype. We conclude that, consistent with their documented role in tumorigenesis, bone marrow c-kit+ cells act as key regulators of the angiogenic switch in infarcted myocardium, thereby driving efficient cardiac repair.
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PMID:Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. 1682 85

Bevacizumab is a humanized monoclonal antibody directed against vascular endothelial growth factor (VEGF-A). Non-Hodgkin's lymphoma patients with high serum VEGF levels have an inferior survival compared to patients with low VEGF levels. Bevacizumab was administered through a central line at 15 mg kg(-1) IV on day 1 followed by rituximab (R) and CHOP on day 2 for cycle 1 and day 1 for cycles 2 - 8. Serum levels of bevacizumab and R were measured at specified time points to assess pharmacokinetics (PK). Plasma and urine samples were also analysed for VEGF. Tumor samples were stained for VEGF, CD31 and factor VIII by immunohistochemistry. Thirteen patients with newly-diagnosed DLBCL received a total of 88 cycles (range 2 - 8, median 7). Best response included five CR, six PR, one SD and one PD with an overall response rate of 85% and complete response rate of 38%. The 12-month PFS is 77% and a median follow-up of 16.9 months for the surviving patients. All tumor samples stained strongly positive for VEGF and there was a marginal association between baseline plasma VEGF and response (p = 0.04). Patients with higher plasma VEGF levels were generally younger and had bulky disease. Micro-vessel density did not correlate with presenting disease characteristics, VEGF expression or response. The PK of bevacizumab and rituximab were not influenced by combined treatment. In this patient population, treatment with RA-CHOP did not result in any episodes of grade 3 or 4 proteinuria, heart failure or hemorrhage. The RA-CHOP combination was generally well tolerated and safe.
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PMID:Rituximab, bevacizumab and CHOP (RA-CHOP) in untreated diffuse large B-cell lymphoma: safety, biomarker and pharmacokinetic analysis. 1684 Jan 82

The vertebrate heart possesses autoregulatory mechanisms enabling it first to sense and then to adapt its force of contraction to continually changing demands. The molecular components of the cardiac mechanical stretch sensor are mostly unknown but of immense medical importance, since dysfunction of this sensing machinery is suspected to be responsible for a significant proportion of human heart failure. In the hearts of the ethylnitros-urea (ENU)-induced, recessive embryonic lethal zebrafish heart failure mutant main squeeze (msq), we find stretch-responsive genes such as atrial natriuretic factor (anf) and vascular endothelial growth factor (vegf) severely down-regulated. We demonstrate through positional cloning that heart failure in msq mutants is due to a mutation in the integrin-linked kinase (ilk) gene. ILK specifically localizes to costameres and sarcomeric Z-discs. The msq mutation (L308P) reduces ILK kinase activity and disrupts binding of ILK to the Z-disc adaptor protein beta-parvin (Affixin). Accordingly, in msq mutant embryos, heart failure can be suppressed by expression of ILK, and also of a constitutively active form of Protein Kinase B (PKB), and VEGF. Furthermore, antisense-mediated abrogation of zebrafish beta-parvin phenocopies the msq phenotype. Thus, we provide evidence that the heart uses the Integrin-ILK-beta-parvin network to sense mechanical stretch and respond with increased expression of ANF and VEGF, the latter of which was recently shown to augment cardiac force by increasing the heart's calcium transients.
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PMID:Integrin-linked kinase, a novel component of the cardiac mechanical stretch sensor, controls contractility in the zebrafish heart. 1695 Dec 48

Pulmonary edema is a life-threatening complication of critical illness. Identification of the underlying mechanisms of pulmonary edema is a prerequisite for the development of adequate treatment. The initial description of fluid transportation across capillaries (Starling's law) while of critical importance, did not provide full insight into the underlying pathophysiology of vascular leakage. Pulmonary edema can be differentiated into two distinct categories based on the Starling theory; the high-permeability type is attributed to inflammatory changes occurring in conditions such as the adult respiratory distress syndrome (ARDS) and the cardiogenic type is characterized by an imbalance in the Starling hydrostatic forces and occurs in acute or decompensated heart failure. However, it has long been recognized that there is significant overlap between the various types of pulmonary edema, raising important questions regarding the role of novel mechanisms that may contribute to the development of interstitial and alveolar leakage. Recently, several studies on VEGF, an angiogenic growth factor which affects endothelial permeability, have identified this molecule as a potential regulator of vascular leakage and repair in pulmonary edema. We review here the underlying the mechanisms by which VEGF may do this and will discuss the still unanswered questions regarding vascular pharmacology in the setting of pulmonary edema.
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PMID:Vascular endothelial growth factors in pulmonary edema: an update. 1755 93

The ischemic etiology of heart failure is an independent prognostic factor associated with worse long-term outcome. Recent evidence indicates a role for genetic susceptibility to ischemic heart failure. The authors systematically reviewed all known case-control studies that investigated the association between genetic variants and ischemic heart failure. Twenty-two articles, which examined 24 gene polymorphisms, were identified. In 22 polymorphisms, the variant form had a functional effect. Twenty-two polymorphisms were variants of genes involved in the maladaptive neurohormonal activation. Seven polymorphisms (ACE I/D, AGT M235T, ADRA2C Del322-325, ADRB2 Arg16Gly, ADRB2 Gln27Glu, EDN1 Lys198Asn, VEGF G-405C) showed a significant association in individual studies. Five polymorphisms (ACE I/D, ADRB1 Arg389Gly, ADRB2 Arg16Gly, ADRB2 Gln27Glu, TNF G308A) were examined by more than one study, and meta-analyses were performed. The meta-analyses showed no significant sign of heterogeneity. In all settings, there was no significant association, except for polymorphism ADRB2 Arg16Gly under a recessive model (fixed-effects odds ratio = 1.32, 95% confidence interval: 1.05, 1.65). Taking into account that ischemic heart failure is a complex disease with multifactorial etiology, a minor contributing pathogenetic role of the investigated gene polymorphisms cannot be totally excluded. Case-control studies that investigate gene-gene and gene-environment interactions might further elucidate the genetics of ischemic heart failure.
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PMID:Genetic variation associated with ischemic heart failure: a HuGE review and meta-analysis. 1764 25

In the past few years, the dogma that the heart is a terminally differentiated organ has been challenged. Evidence from preclinical investigations emerged that there are cells, even in the heart itself, that may be able to restore impaired cardiac function after myocardial infarction. Although the exact mechanisms by which the infarcted heart can be repaired by stem cells are not yet fully defined, there is a new optimism among cardiologists that this treatment will prove successful in addressing the cause of heart failure after myocardial infarction-myocyte loss. Despite the promising preliminary data of human myocardial stem cell trials, scientists have also focused on the possibility of enhancing the underlying mechanisms of stem cell repair to gain healthier myocardial tissue. Attempts to induce neo-angiogenesis by transfecting stem cells with signaling factors (such as VEGF), to raise the number of endothelial progenitor cells with medical treatments (such as statins), to transfect stem cells with heat shock protein 70 (as a cardioprotective agent against ischemia) and to enhance the healing process after myocardial infarction with the use of various forms of stimulating factors (G-CSF, SCF, GM-CSF) have been made with notable results. In this article, we summarize the evidence from preclinical and clinical myocardial stem cell studies that have addressed the possibility of enhancing the regenerative capacity of cells used after myocardial infarction.
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PMID:Drugs, gene transfer, signaling factors: a bench to bedside approach to myocardial stem cell therapy. 1766 19

We previously identified that neuropilin-1 (NP-1) was a co-receptor of vascular endothelial growth factor receptor 2 (VEGFR2) and confirmed that NP-1 knockout mice were embryonic lethal due to impairment of vascular development, while VEGF was reported to be involved in the progression of heart failure. However, it is unknown whether NP-1 has any influence on cardiac function, and it also remains poor understood concerning cardiac expression of NP-1 and its interaction with other VEGF receptors in the heart. Here, we first showed that NP-1 heterozygous mice had significantly higher mortality due to either acute or chronic heart failure in response to left ventricular pressure overload. We also observed that NP-1 mRNA and protein were expressed in both neonatal rat cardiomyocytes and adult murine heart. Furthermore, we found that NP-1 formed complexes with VEGFR1 and VEGFR2, respectively, in cardiomyocytes. These findings suggest that NP-1 should play beneficial role in heart failure.
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PMID:Higher mortality in heterozygous neuropilin-1 mice after cardiac pressure overload. 1838 Oct 67


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